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- Garner, B, et al.
(author)
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On the cytoprotective role of ferritin in macrophages and its ability to enhance lysosomal stability.
- 1997
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In: Free radical research. - : Taylor & Francis. - 1071-5762 .- 1029-2470. ; 27, s. 487-500
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Journal article (other academic/artistic)abstract
- Macrophages have a great capacity to take up (e.g. by endocytosis and phagocytosis) exogenous sources of iron which could potentially become cytotoxic, particularly following the intralysosomal formation of low-molecular weight, redox active iron, and under conditions of oxidative stress. Following autophagocytosis of endogenous ferritin/apoferritin, these compounds may serve as chelators of such lysosomal iron and counteract the occurrence of iron-mediated intralysosomal oxidative reactions. Such redox-reactions have been shown to lead to destabilisation of lysosomal membranes and result in leakage of damaging lysosomal contents to the cytosol. In this study we have shown: (i) human monocyte-derived macrophages to accumulate ferritin in response to iron exposure; (ii) iron to destabilise macrophage secondary lysosomes when the cells are exposed to H2O2; and (iii) endocytosed apoferritin to act as a stabiliser of the acidic vacuolar compartment of iron-loaded macrophages. While the endogenous ferritin accumulation which was induced by iron exposure was not sufficient to protect cells from the damaging effects of H2O2, exogenously added apoferritin, as well as the potent iron chelator desferrioxamine, afforded significant protection. It is suggested that intralysosomal formation of haemosiderin, from partially degraded ferritin, is a protective strategy to suppress intralysosomal iron-catalysed redox reactions. However, under conditions of severe macrophage lysosomal iron-overload, induction of ferritin synthesis is not enough to completely prevent the enhanced cytotoxic effects of H2O2.
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| 5. |
- Li, Wei, et al.
(author)
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OxLDL-induced macrophage cytotoxicity is mediated by lysosomal rupture and modified by intralysosomal redox-active iron
- 1998
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In: Free radical research. - : Informa UK Limited. - 1071-5762 .- 1029-2470. ; 29:5, s. 389-98
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Journal article (peer-reviewed)abstract
- Oxidized low density lipoprotein (oxLDL) is believed to play a central role in atherogenesis. LDL is oxidized in the arterial intima by mechanisms that are still only partially understood. OxLDL is then taken up by macrophages through scavenger receptor-mediated endocytosis, which then leads to cellular damage, including apoptosis. The complex mechanisms by which oxLDL induces cell injury are mostly unknown. This study has demonstrated that oxLDL-induced damage of macrophages is associated with iron-mediated intralysosomal oxidative reactions, which cause partial lysosomal rupture and ensuing apoptosis. This series of events can be prevented by pre-exposing cells to the iron-chelator, desferrioxamine (DFO), whereas it is augmented by pretreating the cells with a low molecular weight iron complex. Since both DFO and the iron complex would be taken up by endocytosis, and thus directed to the lysosomal compartment, the results suggest that the normal contents of lysosomal low molecular weight iron may play an important role in oxLDL-induced cell damage, presumably by catalyzing intralysosomal fragmentation of lipid peroxides and the formation of toxic aldehydes and oxygen-centered radicals.
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- Williams, A., et al.
(author)
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Compromised antioxidant status and persistent oxidative stress in lung transplant recipients
- 1999
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In: Free Radic Res. - 1071-5762. ; 30:5, s. 383-93
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Journal article (peer-reviewed)abstract
- Oxidative stress may be a key feature, and hence important determinant, of tissue injury and allograft rejection in lung transplant recipients. To investigate this, we determined the antioxidant status (urate, ascorbate, thiols and alpha-tocopherol) and lipid peroxidation status (malondialdehyde) in bronchoalveolar lavage (BAL) fluid and blood serum of 19 consecutive lung transplant recipients 2 weeks and 1, 2, 3, 6, and 12 months post-surgery. BAL fluid and blood samples from 23 control subjects and blood from 8 patients two days before transplantation were obtained for comparison. Before surgery, the antioxidant status of patients was poor as serum ascorbate and total thiol concentrations were significantly (p < 0.05) lower than control subjects. Two weeks post-surgery, ascorbate and total thiol concentrations were still low and urate concentrations had fallen compared to control subjects (p < 0.01). At this time, BAL fluid urate concentration was higher (p < 0.01), ascorbate concentration was lower (p < 0.01) and reduced glutathione concentrations were similar to control subjects. MDA, a product of lipid peroxidation, was higher (p < 0.01) in both BAL fluid and serum obtained from transplant patients compared to control subjects. During the first 12 months post-surgery, little improvement in antioxidant status or extent of lipid peroxidation was seen in transplant recipients. Regression analysis indicated no difference in serum or BAL fluid antioxidant status in patients with acute rejection compared to those without. In conclusion, lung transplant recipients have a compromised antioxidant status before surgery and it remains poor for at least the first year following the operation. In addition, these patients have elevated MDA concentrations in both their lung lining fluid and blood over most of this time. Oxidative stress is not, however, a sufficiently sensitive endpoint to predict tissue rejection in this group.
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